A catalogue of works devoted to end-of-life themes. The volume consists of eleven articles arranged in four parts corresponding to a broad range of issues: law, ethics, philosophy, and cultural ...studies. The arrangement of the book is thus constructed around various perspectives upon which any reflection on death and dying must be based.
Recent studies show that cancer cells are sometimes able to evade the host immunity in the tumor microenvironment. Cancer cells can express high levels of immune inhibitory signaling proteins. One of ...the most critical checkpoint pathways in this system is a tumor‐induced immune suppression (immune checkpoint) mediated by the programmed cell death protein 1 (PD‐1) and its ligand, programmed death ligand 1 (PD‐L1). PD‐1 is highly expressed by activated T cells, B cells, dendritic cells, and natural killer cells, whereas PD‐L1 is expressed on several types of tumor cells. Many studies have shown that blocking the interaction between PD‐1 and PD‐L1 enhances the T‐cell response and mediates antitumor activity. In this review, we highlight a brief overview of the molecular and biochemical events that are regulated by the PD‐1 and PD‐L1 interaction in various cancers.
In this review, we highlight a brief overview of the molecular and biochemical events that are regulated by the PD‐1 and PD‐L1 interaction in various cancers.
Neurology ethics at the end of life Mazzola, Maria Antonietta; Russell, James Adams
Handbook of clinical neurology,
2023, Letnik:
191
Journal Article
Recenzirano
Ethical challenges in medical decision making are commonly encountered by clinicians caring for patients afflicted by neurological injury or disease at the end of life (EOL). In many of these cases, ...there are conflicting opinions as to what is right and wrong originating from multiple sources. There is a particularly high prevalence of impaired patient judgment and decision-making capacity in this population that may result in a misrepresentation of their premorbid values and goals. Conflict may originate from a discordance between what is legal or from stakeholders who view and value life and existence differently from the patient, at times due to religious or cultural influences. Promotion of life, rather than preservation of existence, is the goal of many patients and the foundation on which palliative care is built. Those who provide EOL care, while being respectful of potential cultural, religious, and legal stakeholder perspectives, must at the same time recognize that these perspectives may conflict with the optimal ethical course to follow. In this chapter, we will attempt to review some of the more notable ethical challenges that may arise in the neurologically afflicted at the EOL. We will identify what we believe to be the most compelling ethical arguments both in support of and opposition to specific EOL issues. At the same time, we will consider how ethical analysis may be influenced by these legal, cultural, and religious considerations that commonly arise.
PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, ...incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC′ sheet, which is flexible and completely lacks a C″ strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC′ sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1·ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3–4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.
Background: The inhibitory leukocyte receptor PD-1 binds two ligands, PD-L1 and PD-L2.
Results: Nuclear magnetic resonance analysis and rigorous binding and thermodynamic measurements reveal the structure of, and the mode of ligand recognition by, PD-1.
Conclusion: PD-L1 and PD-L2 bind differently to PD-1 and much more weakly than expected.
Significance: Potent inhibitory signaling can be initiated by weakly interacting receptors.
The Routledge History of Death Since 1800 looks at how death has been treated and dealt with in modern history – the history of the past 250 years – in a global context, through a mix of definite, ...often quantifiable changes and a complex, qualitative assessment of the subject.
The book is divided into three parts, with the first considering major trends in death history and identifying widespread patterns of change and continuity in the material and cultural features of death since 1800. The second part turns to specifically regional experiences, and the third offers more specialized chapters on key topics in the modern history of death. Historical findings and debates feed directly into a current and prospective assessment of death, as many societies transition into patterns of ageing that will further alter the death experience and challenge modern reactions. Thus, a final chapter probes this topic, by way of introducing the links between historical experience and current trajectories, ensuring that the book gives the reader a framework for assessing the ongoing process, as well as an understanding of the past.
Global in focus and linking death to a variety of major developments in modern global history, the volume is ideal for all those interested in the multifaceted history of how death has been dealt with in different societies over time and who want access to the rich and growing historiography on the subject.
Caspase-8 activation can be triggered by death receptor-mediated formation of the death-inducing signaling complex (DISC) and by the inflammasome adaptor ASC. Caspase-8 assembles with FADD at the ...DISC and with ASC at the inflammasome through its tandem death effector domain (tDED), which is regulated by the tDED-containing cellular inhibitor cFLIP and the viral inhibitor MC159. Here we present the caspase-8 tDED filament structure determined by cryoelectron microscopy. Extensive assembly interfaces not predicted by the previously proposed linear DED chain model were uncovered, and were further confirmed by structure-based mutagenesis in filament formation in vitro and Fas-induced apoptosis and ASC-mediated caspase-8 recruitment in cells. Structurally, the two DEDs in caspase-8 use quasi-equivalent contacts to enable assembly. Using the tDED filament structure as a template, structural analyses reveal the interaction surfaces between FADD and caspase-8 and the distinct mechanisms of regulation by cFLIP and MC159 through comingling and capping, respectively.
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•Caspase-8 tDED assembles into filaments through quasi-equivalent contacts•The assembly of caspase-8 filaments is nucleated by the upstream Fas/FADD complex•cFLIP tDED also forms filaments, which interact with caspase-8 by comingling•MC159 inhibits caspase-8 filament assembly by a unique capping mechanism
How caspase-8 is activated has been a long-standing question. Fu et al. show that its tDED forms filaments using quasi-equivalent interactions. Cryo-EM structure of the filament reveals mechanisms of caspase-8 activation and its regulation by cFLIP and MC159.
In March 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development held a workshop entitled "Sudden Unexpected Death in Fetal Life Through Early Childhood: New ...Opportunities." Its objective was to advance efforts to understand and ultimately prevent sudden deaths in early life, by considering their pathogenesis as a potential continuum with some commonalities in biological origins or pathways. A second objective of this meeting was to highlight current issues surrounding the classification of sudden infant death syndrome (SIDS), and the implications of variations in the use of the term "SIDS" in forensic practice, and pediatric care and research. The proceedings reflected the most current knowledge and understanding of the origins and biology of vulnerability to sudden unexpected death, and its environmental triggers. Participants were encouraged to consider the application of new technologies and "omics" approaches to accelerate research. The major advances in delineating the intrinsic vulnerabilities to sudden death in early life have come from epidemiologic, neural, cardiac, metabolic, genetic, and physiologic research, with some commonalities among cases of unexplained stillbirth, SIDS, and sudden unexplained death in childhood observed. It was emphasized that investigations of sudden unexpected death are inconsistent, varying by jurisdiction, as are the education, certification practices, and experience of death certifiers. In addition, there is no practical consensus on the use of "SIDS" as a determination in cause of death. Major clinical, forensic, and scientific areas are identified for future research.
Terror management theory (TMT) highlights the motivational impact of thoughts of death in various aspects of everyday life. Since its inception in 1986, research on TMT has undergone a slight but ...significant shift from an almost exclusive focus on the manipulation of thoughts of death to a marked increase in studies that measure the accessibility of death-related cognition. Indeed, the number of death-thought accessibility (DTA) studies in the published literature has grown substantially in recent years. In light of this increasing reliance on the DTA concept, the present article is meant to provide a comprehensive theoretical and empirical review of the literature employing this concept. After discussing the roots of DTA, the authors outline the theoretical refinements to TMT that have accompanied significant research findings associated with the DTA concept. Four distinct categories (mortality salience, death association, anxiety-buffer threat, and dispositional) are derived to organize the reviewed DTA studies, and the theoretical implications of each category are discussed. Finally, a number of lingering empirical and theoretical issues in the DTA literature are discussed with the aim of stimulating and focusing future research on DTA specifically and TMT in general.
Deathscapes Maddrell, Avril, Dr; Sidaway, James D, Professor
2010, 20160513, 2010-12-01, 2016-05-18, 20100101
eBook
Death is at once a universal and everyday, but also an extraordinary experience in the lives of those affected. Death and bereavement are thereby intensified at (and frequently contained within) ...certain sites and regulated spaces, such as the hospital, the cemetery and the mortuary. However, death also affects and unfolds in many other spaces: the home, public spaces and places of worship, sites of accident, tragedy and violence. Such spaces, or Deathscapes, are intensely private and personal places, while often simultaneously being shared, collective, sites of experience and remembrance; each place mediated through the intersections of emotion, body, belief, culture, society and the state. Bringing together geographers, sociologists, anthropologists, cultural studies academics and historians among others, this book focuses on the relationships between space/place and death/ bereavement in 'western' societies. Addressing three broad themes: the place of death; the place of final disposition; and spaces of remembrance and representation, the chapters reflect a variety of scales ranging from the mapping of bereavement on the individual or in private domestic space, through to sites of accident, battle, burial, cremation and remembrance in public space.
The book also examines social and cultural changes in death and bereavement practices, including personalisation and secularisation. Other social trends are addressed by chapters on green and garden burial, negotiating emotion in public/ private space, remembrance of violence and disaster, and virtual space. A meshing of material and 'more-than-representational' approaches consider the nature, culture, economy and politics of Deathscapes - what are in effect some of the most significant places in human society.
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